Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD-1-refractory cancer

Sachin R. Jhawar, Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Shang-Jui Wang, Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Aditya Thandoni, Department of Orthopedic Surgery, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
Praveen K. Bommareddy, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
Jenna H. Newman, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
Amanda L. Marzo, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Timothy M. Kuzel, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Vineet Gupta, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Jochen Reiser, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Preston Daniels, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Devora Schiff, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
Darrion Mitchell, Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Nicole R. LeBoeuf, Harvard Medical School, Boston, Massachusetts, USA.
Christopher Simmons, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Sharad Goyal, Department of Radiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Ahmed Lasfar, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
Jose A. Guevara-Patino, Department of Immunology, Moffitt Cancer Center, Tampa, Florida, USA.
Bruce G. Haffty, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
Howard L. Kaufman, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
Ann W. Silk, Harvard Medical School, Boston, Massachusetts, USA andrewzloza@gmail.com ann_silk@dfci.harvard.edu.
Andrew Zloza, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA andrewzloza@gmail.com ann_silk@dfci.harvard.edu.

Document Type

Journal Article

Publication Date

7-1-2023

Journal

Journal for immunotherapy of cancer

Volume

11

Issue

7

DOI

10.1136/jitc-2023-006780

Keywords

Immune Checkpoint Inhibitors; Oncolytic Viruses; Radioimmunotherapy; Skin Neoplasms

Abstract

BACKGROUND: Immunotherapies are becoming front-line treatments for many advanced cancers, and combinations of two or more therapies are beginning to be investigated. Based on their individual antitumor capabilities, we sought to determine whether combination oncolytic virus (OV) and radiation therapy (RT) may improve cancer outcomes. METHODS: To investigate the activity of this combination therapy, we used in vitro mouse and human cancer cell lines as well as a mouse model of skin cancer. After initial results, we further included immune checkpoint blockade, whose addition constituted a triple combination immunotherapy. RESULTS: Our findings demonstrate that OV and RT reduce tumor growth via conversion of immunologically 'cold' tumors to 'hot', via a CD8+ T cell-dependent and IL-1α-dependent mechanism that is associated with increased PD-1/PD-L1 expression, and the triple combination of OV, RT, and PD-1 checkpoint inhibition impedes tumor growth and prolongs survival. Further, we describe the response of a PD-1-refractory patient with cutaneous squamous cell carcinoma who received the triple combination of OV, RT, and immune checkpoint inhibitor (ICI), and went on to experience unexpected, prolonged control and survival. He remains off-treatment and is without evidence of progression for >44 months since study entry. CONCLUSIONS: Effective systemic antitumor immune response is rarely elicited by a single therapy. In a skin cancer mouse model, we demonstrate improved outcomes with combination OV, RT, and ICI treatment, which is associated with mechanisms involving augmented CD8+ T cell infiltration and IL-1α expression. We report tumor reduction and prolonged survival of a patient with skin cancer treated with combination OV, RT, and ICI. Overall, our data provide strong rationale for combining OV, RT, and ICI for treatment of patients with ICI-refractory skin and potentially other cancers.

Department

Radiology

Link to Full Text

Share

COinS